The present invention relates to pharmaceutical compositions for the treatment of autoimmune-induced glutamatergic receptor dysfunction and disorders related to same. More particularly, the present invention relates to the use of N-methyl-D-aspartate type glutamate receptor (NMDAR) agonists (NMDAR agonists, also known as NMDA agonists) and partial agonists for the treatment of autoimmune-induced glutamatergic receptor encephalitis.
NMDAR are a type of receptor for the excitatory neurotransmitter glutamate. NMDAR contain additional modulatory sites, including the following: glycine binding site, polyamine binding site, redox site, Zinc (Zn) site, phosphorylation sites, post-synaptic membrane docking sites and protein-protein interaction sites. The glycine binding site is sensitive to monocarboxyllic amino acids including the endogenous amino acids glycineD-serine and D-alanine. Glycine is synthesized via serine or threonine by serine hydroxymethyltransferase. Synaptic glycine concentrations are regulated by type 1 (GLYT1) and type 2 (GLYT2) glycine transporters, as well as by other amino acid transporters belonging to Systems A, L, ASC, and N.
GLYT1 transport inhibitors, such as N[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy) propyl] sarcosine (NFPS), potentiate NMDAR activity in vivo, suggesting a critical role for glycine transporters in NMDAR regulation. Methylated glycine derivates (e.g., methylglycine, sarcosine) may serve as non-specific glycine transport inhibitors D-serine and D-alanine are metabolized by D-amino acid oxidase (DAAO), which is localized particularly in hindbrain. Further, DAAO is regulated by a novel protein termed G72, which may affect metabolic activity of the DAAO enzyme.
Glycine, D-serine and D-alanine levels in brain may be modulated by administering exogenous compound (i.e., glycine, D-serine or D-alanine), or naturally occurring precursors to these compounds including but not limited to L-serine, L-phosphoserine, D-phosphoserine and threonine, or by modulation of the synthetic enzymes serine hydroxymethyltransferase or serine racemase. D-Serine or D-alanine levels may also be increased by modulation inhibiting D-serine or D-alanine breakdown, for example, by antagonizing DAAO activity either directly or indirectly (e.g., via modulatory proteins).
Limbic encephalitis (LE) refers to an inflammatory process that predominantly affects the grey matter of the medial temporal lobes, amygdala and orbito-frontal cortex and produces cognitive impairment along with emotional and behavioral disturbances, sleep disruption, seizures and sometimes dementia. Until recently, autoimmune LE was mostly viewed as a paraneoplastic disorder associated with onconeural antibodies to intracellular antigens, cytotoxic T-cell mediated pathogenesis and limited response to treatment. However, accumulating data suggest that the clinical and immunological spectra of LE are far more extensive than initially considered. During the last decade a novel category of autoimmune encephalitides has emerged, that is characterized by antibodies against neuronal cell surface antigens, less frequent association with cancer, an antibody-mediated pathogenesis and improved treatment response following immunotherapy. Receptors and proteins that are critically involved in glutamatergic neurotransmission and synaptic plasticity, including N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazol-propionic acid receptors (NMDAR, AMPAR) are cardinal target antigens in many of these disorders. Characteristic of these syndromes, the antibodies alter the structure and/or function of the corresponding neuronal antigen resulting in clinical pictures that resemble the pharmacological or genetic models in which the antigen is disrupted. Given the involvement of glutamatergic neurotransmission in a variety of psychiatric disorders, including schizophrenia and affective disorders, the identification of specific autoimmune-induced glutamatergic receptor dysfunctions (AGRD) is likely to have a substantial conceptual impact upon our understanding of neuropsychiatric disorders and to provide additional guidance for psychiatric diagnostics and treatments development.
NMDAR play a key role in the regulation of movement and striatal function and in the modulation of executive functions and effect. NMDARs are found on multiple classes of neuron within striatum including projection neurons and internuerons. NMDARs are composed of multiple subunits including an NR1 subunit which is present in virtually all functional NMDARs, and NR2 subunits that are present in variable proportions. Four NR2 subunits (NR2A-D) have been described. NR2A expression is high in GABAergic neurons that express the marker GAD67, intermediate over SP neurons, low in ENK neurons, not found in cholinergic and SOM neurons. In contrast, NR2B expression is intense in all populations of neurons, while expression of NR2C,D is weak
The existence of multiple subforms of NMDAR in striatum is supported by the observation that NMDARs controlling GABA and DA release are less sensitive to NMDA than receptors controlling spermidine or ACh release.
Anti-NMDAR encephalitis is an autoimmune encephalitis characterized by the presence of antibodies against synaptic NMDAR. Anti-NMDAR encephalitis has become the most common and best characterized antibody-defined autoimmune neuronal disorder. Nevertheless, additional AGRD syndromes, associated with the presence of antibodies against diverse GLU neurotransmission-related antigens, including different NMDAR subunits, AMPAR and metabotropic receptor proteins are being increasingly characterized. Furthermore, the presence of NMDAR and AMPAR directed antibodies in conjunction with antibodies to different other types of receptors and neurotransmission systems has been reported. Overall, in view of the impact and interest generated by these findings, it is likely that during the next decade we will witness a significant expansion in the identification, characterization and understanding of AGRD.
The encephalitis associated with antibodies against NMDAR predominantly affects children and young adults, occurs with or without tumor association, responds to treatment but can relapse. The presence of a tumor (usually an ovarian teratoma) is dependent on age, sex and ethnicity, being more frequent in women older than 18 years and black women.
The exact incidence of anti-NMDAR encephalitis is unknown but it seems to be more frequent than any other known paraneoplastic encephalitis. Furthermore, due to the rareness of the syndrome and the varied clinical presentations ranging from psychiatric and neurological manifestations to autonomic dysregulation, the anti-NMDAR syndrome is still misdiagnosed and under-recognized.
Few laboratory diagnostic tests are available for anti-NMDAR encephalitis and related syndromes. The most accurate diagnostic finding is the presence of antibodies against NMDAR in the serum or CSF. Serum and CSF of patients suspected with the syndrome should be checked for reactivity with the hippocampal tissue on rat brain sections, cell-surface labeling of cultured hippocampal neurons, or reactivity with NR1/NR2 transfected human embryonic kidney (HEK) cells. The CSF may also present pleocytosis, increased protein concentration, oligoclonal bands and high IgG index. In vitro and in vivo studies demonstrate that patients antibodies decrease the surface density and synaptic localization of NMDAR clusters via antibody mediated capping and internalization, independent of the presence of complement, and without affecting other synaptic proteins, AMPARs or synapse density. The magnitude of these changes depends on antibody titer, and the effects are reversible when the antibody titer is reduced. Moreover, patients NR1 antibodies decrease NMDAR-, but not AMPAR-mediated synaptic currents.
This reversible NMDARs loss, and the resulting synaptic dysfunction, may underlie the deficits in memory, behavior and cognition that are hallmarks of anti-NMDAR encephalitis. Indeed, a remarkable feature of this disorder is the frequent reversibility of symptoms, even when these are severe and protracted. A decrease in serum antibody titers was demonstrated in parallel to immuno-modulatory treatment and clinical remission. Consequently, the effectiveness of therapeutic strategies may be assessed individually by quantitative determination of anti-NMDAR antibodies.
Other tests that can be done to support the diagnosis are electroencephalogram and MRI. Electroencephalogram can frequently demonstrate focal or diffuse slow activity during episodes of dyskinesias or abnormal movements and less commonly it may show epileptic activity. In many patients, MRI shows small areas of Fluid Attenuated Inversion Recovery (FLAIR) abnormalities in cerebral cortex outside the medial temporal lobes, sometimes involving the cerebellum and brainstem or transient enhancement of overlying meninges.
Immunotherapy and the detection and removal of a tumor (mostly teratoma) are the most important components in the treatment of anti-NMDAR encephalitis. Rosenfeld and Dalmau have proposed a structured treatment approach to patients with synaptic autoimmunities such as anti-NMDAR encephalitis. First, search for and remove a tumor. After tumor removal or if no tumor is found, 5-days course of concurrent IV Ig and methyl prednisolone should be given. If clear improvement is seen within 10 days, supportive care should be continued. If there is no response or limited response after one cycle of immunosuppression, cyclophosphamide (monthly) and rituximab (weekly for 4 weeks starting with the first dose of cyclophosphamide) should be initiated. For patients with limited or no response to these approaches, other forms of immunosuppression should be considered. For patients without tumors, immunosuppression with mycophenolate mofetil or azathioprine for at least one year after initial treatments should be considered, to reduce the high rate of relapses after recovery.
In patients without a tumor or with delayed diagnosis, additional treatment with second-line immunotherapy (rituximab or cyclophosphamide, or both) is usually needed with equivocal results. Relapses of anti-NMDAR encephalitis occur in 20% to 25% of treated patients, as well.
An accepted treatment of the syndrome is immunomodulation, which inadequately addresses the alleviation of psychiatric manifestations. There are several documented cases of neuroleptic administration actually exacerbating neuropsychiatric symptoms and movement abnormalities. ECT has been used for targeting catatonic presentations in patients with autoimmune encephalitis, including anti-NMDAR encephalitis. Agitated aggression has been treated with various conventional and atypical antipsychotics with limited treatment response. Atypical antipsychotics have also been used to target psychotic symptoms without significant success and have the potential to worsen dyskinesia and other movement abnormalities.
Thus there remains a need for the development of an appropriate therapeutic for encephalitis associated with antibodies against NMDAR, which is as yet lacking.